Arsenical compounds and methods for obtaining the same



Patented Sept. 4, 1951 ARSENICAL COMPOUNDS AND METHODS FOR OBTAINING THE SAME Leon A. Sweet and Edward W. Tillitson, Grosse Pointe, Mich., assignors to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application September 17, 1947,

Seriai'No. 774,676

6 Claims. (Cl. 260-440) This invention relates to a new class of sulfur- -containing arsenical compounds and to methods for obtaining the same. More particularly, the invention relates to a class of compounds having the formula,

o s-cHlo B As N'Hi CH2 CH 011 Where R is OH, --O-alkyl of 1 to 12 carbons inclusive or NH2.

The compounds of the present invention may be obtained in the non-salt form having the formula given above or in the form of their acid addition salts with strong acids such as hydrochloric, hydrobromic, sulfuric, citric, tartaric and the like acids. The products containing acidic groups, that is, the carboxyl groups, can be obtained in the form of their alkali metal salts as well as in their non-salt and acid addition salt forms.

In accordance with the invention the new sulfur-containing arsenic compounds are obtained by reacting a mercapto acid compound of the formula,

Hs-cmo with a 3-amino-4-p-hydroxyethoxybenzene arsenic compound of the formula,

CH CHzOH where R has the same significance as given above and X is As0, As0aH2, --As(OH)2, AsC12 and --AsBrz. In general, the reaction is eflected 2 merely by mixing the two reactants in a solvent such as water, alcohols, lower aliphatic ketones, dioxane or mixtures of the same. Several different methods may be used to isolate the product from the reaction mixture. For example, when the reaction is carried out in a non-aqueous solvent such as ethanol the free base may be obtained by evaporation of the reaction mixture to dryness. Alternatively, the product may be precipitated as an acid addition salt by adding an equivalent amount of acid to the alcoholic reaction mixture and the free base obtained by neutralization of an aqueous solution of the salt. When the product contains a carboxyl group it can be isolated as an alkali metal salt. This may be accomplished, for example, by adding an organic solvent such as alcohol to the aqueous reaction mixture.

When 3 amino-4-fl-hydroxyethoxybenzenearsonic acid is used as the starting material, four equivalents instead of the customary two equivalents of the mercapto acid compound are required. Two of the equivalents of the mercapto acid compound function as a reducingagent to first reduce the arsonic acid to the arsonous acid which then reacts with the other two equivalents of the mercapto acid compound. The oxidized mercapto acid compound formed during the reaction appears in the reaction mixture as the disulfide which in most instances is soluble in the reaction mixture.

The new sulfur-containing arsenic compounds and their salts are useful therapeutic agents and find particular application as trypanocidal and spirocheticidal agents. The preferred compounds of the invention are the alkyl esters containing about 6 to 12 carbon atoms in the alkyl radicals.

Such products are especially valuable due to their 1 3 Example 1.(3-amino-4 s-hydromyethoryphenyl) di- (carboxymethylmercapto) arsine adjusted to 7 with 10 N sodium hydroxide som tion. Seven volumes of ethanol. are added andthe crystalline sodium salt of (3-amino-fl-fl-hy droxyethoxyphenyl) di- (carboxymethylni'erc'ap to) arsine which separates collected.

When potassium hydroxide is substituted for the sodium hydroxide used in the above procedure one obtainsthepotassium salt of (B -:amino-fl-fihydroxyethoxyphenyl) di (carboxymethylmercapto)-arsine. H d v g. of the sodiumsalt of (B-aminOil-Ii- Y- droxyethoxyphenyl) di- (carboxymethylmercapto).arsine is dissolved ina small amount of water and the solutiontreated with two equivalentsof dilutehydrochloric acid. The free 3-amino- 4- ,B-hydroxyethoxyphenyl) di-(carboxymethylmercapto arsine which separates is collected and recrystallized from water. d A

(b) An absolute ethanol solution of l8 41g. of mercaptoacetic acid is added to a solutionof 26.1 g. of 3-amino-4-;8-hydroxyethoxybenzenearsonous acid in absolute'ethanol with stirring. The free (3-aminor4rB-hydroxyethoxyphenyl) di-(c arboxymethylmercaptomrsine present in the solution is converted to the hydrochloride salt by the addition of dry hydrogen chloride gas with cooling. The crystalline hydrochloride salt of (3- amino-4-v B -hydroxyethoxyphenyl) di-(carboxymethylmercapto)arsine which separates is collected; washed with a small amount of alcohol and dried.

ramps 2.-- 3 amino- 4 s hy rdx' tadi phenyl) di- (carboctyloxymethylmercapto) arsine CHiOHzOH n An absolute ethanol solution of 40.8 g. of noctyl mercaptoacetate is added s owly withstlrring" to 26.1 g. of 3- amino 4-c-hydroxyethoxy benzenarsonous acid ssolve in a minimal amount of absolute ethanol. Thefree base of the desired 3-amino#i fi-hydroxyethoxyphenyl) di-(carboctyloxymethylmercapto) arsine can r be isolated by evaporation'oi the solvent underre duced pressure or the base may be converted to the hydrochloride salt by addition of dry hydrogen chloride gas to the alcoholic solution: The

4 white hydrochloride salt which separates from the solution in crystalline form is collected, washed with a small amount of alcohol and dried.

Erample 3.-(3 amino 4 [3 hydrozryethomij phenyl) dz- (carbomethoxymethylmerccpto) arsine CHzOH An alcoholic solution containing 21.2 g. of

methylmercaiitoacetate is added With stirring to an absolute alcohol solution of 26.1 g. of 3-amino- 4-B hydroxyethoxybenzenearsonous acid. The free (3-amino-4- B -hydroxyethoxyphenyl) di- (carbomethoxymethylmercapto) arsine Which-1 remains dissolved in the solution is precipitatedas.

the hydrobromide salt by .theaddition' of dry gaseous hydrogen bromide with: cooling. The white, crystalline salt is c0llected, wa-shed with a small amount of ethanol and dried. If desired, the free base may be obtained by dissolving the hydrobromide salt in water and adding an equivalent of dilute sodium hydroxide solution. The

free base which precipitates is collected, washed with a little water and dried.

When ethyl mercaptoacetate is substituted in the above procedure for the methylmercaptoacetate one obtains (3-aminof4-B hydroxyethoxyphenyl) di- (carbethoxymethylmercapto) arsine.

In a similar manner when isopropyl mercaptoacetate is used one obtains (3-amino-4-B-hydroxy'ethoxyphenyl) di (carbisoijropoxymethyl mercapto)arsine.

' Emma dens-ammo a 4 sz htd'rbwyethomyphenyl) di (curb -2 -ethylheazgjlomymethylmer captomrsi'ne H CH5 /s cHio -oonzofiomomomcm SCH2 OCH;CHCH2CH1CH2OH;

omomon 40.4 g. of 2-ethylhexyl mercaptoacetate dissolved in absolute ethanol is added to an absocollected, washedwith water and dried;

Example 5.-=7(3-amino-4-fi-hydroa:yethoxyphenyl) di-(carbamidomethylmercapto)arsine 18.2 g. of p-mercaptoacetamide is added to an aqueous solution containing 26.1 g. of 3-amino- 4-B-hydroxyethoxybenzenearsonous acid and the N sodium hydroxide solution added to the mixture until the pH reaches a value of about 8. The crude free base of (3-amino-4-B-hydroxyethoxyphenyl) di-(carbamidomethylmercapto) arsine which separates is collected, dissolved in absolute ethanol and treated with an excess of dry hydrogen chloride gas. The hydrochloride salt which separates is collected, Washed with alcohol and dried.

Example 6.-(3-amino-4-p-hydroryethoamphenyl) dz (curb-1-methylheptyloa:ymethylmercapto) arsine OCHzCHzOH A solution of 40.8 g. of l-methylheptyl mercaptoacetate in absolute ethanol is added to an absolute ethanol solution of 24.3 g. of 3-amino-4- fl-hydroxyethoxybenzene arsine oxide with stirring. The reaction mixture is evaporated to about one-half volume under reduced pressure and the residue treated with an excess of dry hydrogen chloride gas. The hydrochloride salt of the desired product which separates on cooling is collected, washed with a small amount of alcohol and dried. The crude hydrochloride salt is dissolved in water and the solution made alkaline with 10% sodium hydroxide solution. The free base of (3-amino-4-B-hydroxyethoxyphenyl) di-(carb 1' methylheptyloxymethylmercapto) arsine which precipitates is collected, washed with water and dried.

Example 7.-(3-amin0-4-p-hydro:ryethoa:yphenyl) di-(carbodecyloxymethylmercapto) arsine OHrOHzdH 46.4 g. of n-decyl mercaptoacetate in absolute ethanol is added to an absolute ethanol solution containing 31.8 g. of dichloro (S-amino-Q-fi-by- CHgCHzOH and non-toxic acid addition salts thereof, where alkyl contains 6 to 12 carbon atoms. 2. A compound of the formula,

CHzCHaOH and non-toxic acid addition salts thereof.

3. A compound of the formula, 5

O C2110 ('5 t /S-CH -ocH H-CHSCH2CH2CHI As O t s-om -0CHaCHCH9CHzCH CH;

and non-toxic acid addition salts thereof.

4. A compound of the formula,

0 02115 s-oHl -o 0m(':H-omoHlcHzoH,

\SCH%0CH2CHCH5CH;CH1CH;

N'Ha

CHzCHaOH 5. A compound of the formula,

CHzCHzOH and non-toxic acid addition salts thereof.

7 s Aaomfioumi-of the-fcsrmula, REFERENCES CITED 5' CH3 V V The following references are of record iri the s 0112 0-cpg cmomomomcmom file of thls Patent: 1 As 0 V E V; UNITED STATES PATENTS E CHF -O-CELCHQomcmomcmcm Number Name Date H 1 1,909,498 Oechslin May 16, 1933 s: v 5 2,209,876 Ewins et al' July 30, 1940 NH I 2,331,833 Hamilton Oct. 12, 1943 E FOREIGN PATENTS 0112011103 v Number Country Date AQSWEET. 331,195 Great Britain of 1930 EDWARD W. TILLI'ISON. 

1. A COMPOUND OF THE FORMULA 